The Expression of TLR-4 and 9 is increased and correlated with the expression of IL-17, Interferon-Gamma and TNF-Alpha in patients with Idiopathic Inflammatory Myopathies - OP0058
Authors: S. Baek 1, J. Lee 1, J. Lee 1, M. Cho 1, S. Kim 2, J. Kim 1, G. Kim 1, D. Kim 3, S. Kim 3. 1Internal medicine, Pusan National University Hospital, Busan, 2Internal medicine, Ulsan University, Gangneung, 3Neurology, Pusan National University Hospital, Busan, South Korea
Background:
Idiopathic inflammatory myopathies (IIM) are systemic autoimmune diseases characterized by inflammatory infiltrates in muscle tissues. Immune cells (macrophages, T and B lymphocytes) interact with resident mesenchymal cells (myoblast/myotube) through cell–cell contact and/or the release of soluble factors leading to muscle inflammation and destruction. IL-17 (produced by Th 17 CD4+ cells), Interferon (IFN)-gamma (produced by Th1 CD4+ cells) and TNF-alpha (produced by inflammatory monocytes) play important roles in IIM. Toll-like receptors (TLRs) are presented in innate immune cells and activation of TLRs is involved in development of autoimmune and chronic inflammatory disease.
Objectives:
To investigate the expression of TLR-4 and 9, and IL-17, IFN-gamma and TNF-alpha in IIM.
Methods:
TLR-4, 9, and IL-17, IFN-gamma and TNF-alpha expressions were determined by real-time RT-PCR from muscle tissues in 14 patients with IIM (5 patients with polymyositis (PM), 9 patients with dermatomyositis (DM)) and 3 healthy controls. The expression levels were compared between patients and healthy control. TLR-4 and 9 expressions were also determined by immunohistochemistry.
Results:
In immunohistochemistry, TLR-4 and 9 are mainly expressed on sarcolemma of muscle fibers, perimysial vascular endothelium and infiltrating inflammatory cells in DM, whereas, they were mainly expressed on sarcolemma of muscle fibers, destructed muscle fibers, and enodmysial infiltrating inflammatory cells in PM. The relative expression ratio of TLR-4 (170±105 fold), TLR-9 (19±14 fold), IL-17 (66±61 fold), IFN-gamma (1121±978 fold), and TNF-alpha (23±22 fold) in IIM were significantly higher than healthy controls(Table 1). The expression of TLR-4 and 9 was significantly correlated with the expression of IL-17 (R2 of TLR-4 and TLR-9 is 0.9, p<0.01, respectively), IFN-gamma (R2 of TLR-4 and TLR-9 is 0.8, p<0.01, respectively) and TNF-alpha (R2 of TLR-4 and TLR-9 is 0.7, p<0.01, respectively).
Conclusion:
The expression of TLR-4 and 9 was significantly increased in muscle tissue of patients with IIM compared to healthy control, and was significantly correlated with the expression of IL-17, IFN-gamma and TNF-alpha. These results suggest that enhanced TLR-4 and 9 expression may be involved in immunopathogenesis of IIM.
Comment:
The roll of toll-like receptors in the pathogenesis of autoimmune diseases is becoming better understood – especially in rheumatoid arthritis and systemic lupus erythematosus. The association with autoimmune myopathies is less well understood. This study demonstrates that TLR-9 and TLR-4 are significantly increased in muscle tissue in PM and DM and in the perimysial vascular endothelium in DM when compared to healthy controls. The expression was correlated with IL-17, INF-gamma, and TNF-alpha expression – which helps to explain the mechanism of inflammation. In the clinical arena, toll-like re receptor inhibition is a potential new target against which we can direct therapy.